This invention relates to pharmaceutical combinations of a xcex3-aminobutyric acid (GABA) agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a sorbitol dehydrogenase inhibitor (SDI), a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. This invention also relates to additive and synergistic combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, whereby those additive and synergistic combinations are useful in treating mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers.
GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. Its receptors have been divided into two main types. The more prominent GABA receptor subtype, the GABAA receptor, is a ligand-gated Cl31 ion channel that is opened after release of GABA from presynaptic neurons. A second receptor, the GABAB receptor, is a member of the G protein-coupled receptor family coupled both to biochemical pathways and to regulation of ion channels. (Goodman and Gilman""s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N. Y., 9th Edition, (1996).
By gating negative chloride (Cl31) ions into the interior of cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. Such inhibition is extremely common: GABA receptors can be found in 60-80% of central nervous system neurons. Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at GABAA) as well as the antispasmodic amino acid baclofen (GABAB). These compounds directly mimic the action of GABA at the receptor. Allosteric facilitation of GABA receptors occurs at several distinct sites; the compounds which bind there are used as sedatives and anxiolytics. Progabide is a prodrug which decomposes to GABA after crossing the blood/brain barrier into the central nervous system. Vigabatrin (gamma-vinyl-GABA) promotes binding of GABA by inhibiting GABA-aminotransferase (GABA-T), the enzyme responsible for degrading GABA in the synapse.
GABA agonists well known in the art include muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin(copyright)), vigabatrin, valproic acid, tiagabine (Gabitril(copyright)), lamotrigine (Lamictal(copyright)), pregabalin, phenytoin (Dilantin(copyright)), carbamazepine (Tegretol(copyright)), topiramate (Topamax(copyright)) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of those GABA agonists. It will be recognized by those skilled in the art in light of this disclosure that other GABA agonists are also useful in the combinations, pharmaceutical compositions, methods and kits of this invention. GABA agonists have been disclosed to be useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington""s chorea, cerebral ischemia, Parkinson""s disease, tardive dyskinesia and spasticity. GABA agonists have also been disclosed to be useful as antidepressants, anxiolytics and antipsychotics. Further, GABA agonists have been disclosed to have utility in the treatment of pain.
S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578, which are hereby incorporated by reference, each disclose compounds of the Formula A, 
wherein R1 through R5 in the compound of Formula A are defined as disclosed therein. Further, U.S. Pat. No. 5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Commonly assigned International Patent Application Publication Number WO00/59510, which is incorporated herein by reference, discloses compounds of the formula 
wherein R1 through R3 in the compound of Formula I are defined as disclosed therein. That application discloses that the compounds of Formula I have utility in the treatment of diabetic complications.
This invention is directed to pharmaceutical compositions comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug;
b. an amount of a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug; and, optionally,
c. a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to kits for achieving a therapeutic effect in a mammal comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a first unit dosage form;
b. an amount of a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug;
wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal a pharmaceutical composition comprising
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug; and, optionally,
(c) a pharmaceutically acceptable vehicle, carrier or diluent.
The methods of this invention include therapeutic treatment of diabetic complications. Diabetic complications which may be treated by the methods of this invention include, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts and foot ulcers. Humans are especially preferred mammals which are treated by the methods of this invention.
Preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention are compounds of Formula I, 
prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
R1 is formyl, acetyl, propionyl, carbamoyl or xe2x80x94C(OH)R4R5;
R4 and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C1-C3)alkyl;
R2 is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy;
R3 is a radical of the formula 
wherein said radical of formula R3a is additionally substituted on the ring by R6, R7 and R8;
said radical of formula R3b is additionally substituted on the ring by R18, R19 and R20; G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, xe2x80x94(Cxe2x95x90NR10)xe2x80x94, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C1-C4)alkylenylcarbonyl, sulfonyl-(C1-C4)alkylenylcarbonyl or carbonyl(C0-C4)alkylenylcarbonyl; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl and thio(C1-C4)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; and said carbonyl(C0-C4)alkylenylcarbonyl in the definition of X is optionally substituted indepedently with up to three (C1-C4)alkyl, benzyl or Ar;
R10 is hydrogen or (C1-C4)alkyl;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C3)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro; provided that when q=0 and X is a covalent bond, oxycarbonyl or (C1-C4)alkylenylcarbonyl, then R9 is not (C1-C6)alkyl;
Ar and Ar1 are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
Ar and Ar1 are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R11, R12, R13 and R14; wherein R11, R12, R13 and R14 are each taken separately and are each independently halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R15R16, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C0-C4)alkylsulfamoyl, N-(C0-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, N-phenylcarbamoyl, N-(C1-C4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C1-C4)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definition of R11, R12, R13 and R14 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of R11, R12, R13 and R14 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from (C1-C4)alkyl; said pyrrolidinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C1-C3)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to three substituents independently selected from (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, (C0-C4)alkylsulfamoyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy-(C2-C3)alkyl or (C1-C4)alkyl optionally substituted with up to five fluoro; and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R11, R12, R13 and R4 are optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C0-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R11 and R12 are taken together on adjacent carbon atoms and are xe2x80x94CH2OC(CH3)2OCH2xe2x80x94 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94, and R13 and R14 are taken separately and are each independently hydrogen or (C1-C4)alkyl;
p is 1, 2 or 3;
R15 and R16 are taken separately and are each independently hydrogen, (C1-C4)alkyl optionally substituted with up to five fluoro; or R15 and R16 are taken separately and R15 is hydrogen and R16 is (C3-C6)cycloalkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R15 and R16 are taken together and are (C3-C6)alkylene;
G3, G4 and G5 are taken separately and are each hydrogen; r is 0; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently (C1-C4)alkyl; or
G3, G4 and G5 are taken separately and are each hydrogen; r is 1; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4) wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and
R20 are each independently hydrogen or (C1-C4)alkyl; or
G3 and G4 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G5 are hydrogen; or
G4 and G5 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G3 are hydrogen;
R17 is SO2NR21R22, CONR2R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkycarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2xe2x80x94(C0-C4)alkylenyl; or
R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optional substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar2 is independently defined as set forth for Ar and Ar1 above;
said Ar2 is optionally independently substituted as set forth for Ar and Ar1 above;
R23CONR25R26 or SO2OR25R26 wherein R25 is hydrogen (C1-C4)alkyl or Ar3xe2x80x94(C0-C4)alkylenyl and R26 is Ar3xe2x80x94(C0-C4)alkylenyl; provided that when Ar3 is phenyl, naphthyl or biphenyl, then R23 cannot be CONR25R26 where R25 is hydrogen or Ar3 and R26 is Ar3;
R24 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
Ar3 is independently defined as set forth for Ar and Ar1 above;
said Ar3 is optionally independently substituted as set forth for Ar and Ar1 above;
R27 is hydrogen or (C1-C4)alkyl;
R28 and R29 are each independently hydrogen, hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO2NR30R31, CONR30R31 or NR30R31; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R28 and R29 are optionally substituted by up to two hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R28 and R29 are optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R30 and R31 are each independently hydrogen, (C1-C4)alkyl, (C3-C7)cycloalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R30 and R31 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R30 and R31 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R30 and R31 are optionally substituted with up to three hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R30 and R31 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C1-C4)alkyl and B is carbonyl; or
A is carbonyl and B is N optionally substituted with hydrogen or (C1-C4)alkyl;
R32 is hydrogen or (C1-C4)alkyl;
R33 is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R33 are optionally substituted with up to three phenyl, phenoxy, NR34R35, halo, hydroxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alky optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R34 and R35 are each independently hydrogen, (C1-C4 alkyl), phenyl or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition of R34 and R35 are optionally substituted with up to three halo, hydroxy, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CH2;
E is O, NH or S;
R36 and R37 are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, pyrrolidino, piperidino, morpholino, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, Ar4, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R38, R39 and R40 are each independently hydrogen or (C1-C4)-alkyl;
Ar4 is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; said Ar4 being optionally substituted with up to three hydroxy, (C1-C4)alkoxy-(C1-C4)alkyl, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R36 and R37 are taken together on adjacent carbon atoms and are xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94;
t is 1, 2 or 3;
Y is (C2-C6)alkylene;
R44, R45 and R46 are each independently hydrogen or (C1-C4)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0, 1, 2, 3 or 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar1 above;
Ar5 is optionally independently substituted as set forth for Ar and Ar1 above;
R42 and R42a are independently hydrogen, (C3-C7)cycloalkyl, Ar6xe2x80x94(C0-C3)alkylenyl, Ar6xe2x80x94(C2-C4)alkenyl, Ar6-carbonyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar6 is independently defined as set forth for Ar and Ar1 above;
Ar6 is optionally independently substituted as set forth for Ar and Ar1 above; and
R41 and R41a are each independently hydrogen or (C1-C4)alkyl.
More preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention are compounds of Formula I of the immediately preceding paragraph, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
R1 is C(OH)R4R5, where R4 and R5 are each independently hydrogen or methyl;
R2 is hydrogen;
R3 is 
wherein said R3 is substituted by R6, R7 or R8;
G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen or (C1-C4)alkyl; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, thio(C1-C4)alkylenylcarbonyl or vinylenylsulfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; said oxy(C1-C4)alkylenylcarbonyl and said thio(C1-C4)alkylenylcarbonyl in the definition of X are optionally substituted with up to two (C1-C4)alkyl, benzyl or Ar;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C4)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; and
said Ar1 is optionally substituted as set forth above in the definition of the variables of the compounds of Formula I.
Still more preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention are compounds of Formula I of the immediately preceding paragraph, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
X is a covalent bond, oxycarbonyl or vinylenylcarbonyl optionally substituted on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar;
R9 is Ar1xe2x80x94(C0-C4)alkylenyl;
Ar1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, furanyl, thienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, furopyridyl, oxazolopyridyl, thiazolopyridyl, thienopyridyl, furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or thiazolopyrimidyl; and
said Ar1 is optionally substituted as set forth above in the definition of the variables of the compounds of Formula I.
Still more preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention are compounds of Formula I of the immediately preceding paragraph, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
R2 is hydrogen;
R4 is hydrogen or methyl;
R5 is methyl;
G, G1 and G2 are hydrogen;
R6 and R7 are each independently hydrogen or methyl;
R8 is hydrogen.
Particularly preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention include:
R-(4-{1xe2x80x2-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4xe2x80x2]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;
(4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5-S-dimethyl-piperazin-1-yl}-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yl-methanone;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 5-chloro-pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester;
(E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-3-thiophen-2-yl-propenone;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2yl}-ethanol;
1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;
1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;
1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl }-pyrimidin-2-yl)-ethanol;
1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-y)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;
1-(-4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;
1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs.
More particularly preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention include:
1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; (4-4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl-ethanol; and 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs.
Preferred GABA agonists for use in the combinations, pharmaceutical compositions, methods and kits of this invention include: muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin(copyright)), vigabatrin, valproic acid, tiagabine (Gabitril(copyright)), lamotrigine (Lamictal(copyright)), pregabalin, phenytoin (Dilantin(copyright)), carbamazepine (Tegretol(copyright)), topiramate (Topamax(copyright)), prodrugs thereof and pharmaceutically acceptable salts of said GABA agonists and said prodrugs.
More preferred GABA agonists for use in the combinations, pharmaceutical compositions, methods and kits of this invention include gabapentin, tiagabine, lamotrigine, phenytoin, carbamazepine, topiramate, pregabalin, prodrugs thereof and pharmaceutically acceptable salts of said GABA agonists and said prodrugs.
A particularly preferred GABA agonist for use in the combinations, pharmaceutical compositions, methods and kits of this invention is pregabalin, a prodrug thereof or a pharmaceutically acceptable salt of said pregabalin or said prodrug.
Another particularly preferred GABA agonist for use in the combinations, pharmaceutical compositions, methods and kits of this invention is gabapentin (Neurontin(copyright)), a prodrug thereof or a pharmaceutically acceptable salt of said gabapentin (Neurontin(copyright)) or said prodrug.